This phase II, single-arm, multicenter study examined the efficacy and safety of coltuximab ravtansine (an anti-CD19 antibody drug conjugate) in 61 patients with histologically documented (de novo or transformed) relapsed or refractory diffuse large B-cell lymphoma who had previously received rituximab-containing immuno-chemotherapy. Patients had received a median of 2.0 (range 0-9) prior treatment regimens for diffuse large B-cell lymphoma and almost half (45.9%) had bulky disease (≥1 lesion >5 cm) at trial entry. Patients received coltuximab ravtansine (55 mg/m2) in 4 weekly and 4 biweekly administrations until disease progression or unacceptable toxicity. Forty-one patients were eligible for inclusion in the per protocol population. Overall response rate (International Working Group criteria) in the per protocol population, the primary end point, was 18/41 [43.9%; 90% confidence interval (CI:) 30.6-57.9%]. Median duration of response, progression-free survival, and overall survival (all treated patients) were 4.7 (range 0.0-8.8) months, 4.4 (90%CI: 3.02-5.78) months, and 9.2 (90%CI: 6.57-12.09) months, respectively. Common non-hematologic adverse events included asthenia/fatigue (30%), nausea (23%), and diarrhea (20%). Grade 3-4 adverse events were reported in 23 patients (38%), the most frequent being hepatotoxicity (3%) and abdominal pain (3%). Eye disorders occurred in 15 patients (25%); all were grade 1-2 and none required a dose modification. Coltuximab ravtansine monotherapy was well tolerated and resulted in moderate clinical responses in pre-treated patients with relapsed/refractory diffuse large B-cell lymphoma. (Registered at: clinicaltrials.gov identifier: 01472887).

Azienda Ospedaliera Papa Giovanni XXIII Bergamo Italy

Boise VA Medical Center Boise ID USA

Charles University General Hospital Prague Czech Republic

Department of Hematology and Oncology University Hospital Brno Czech Republic

Department of Hematology University Hospital Leuven Belgium

Ernest and Helen Scott Haematological Research Institute University of Leicester UK

Fondazione Istituto Nazionale Tumori Milan Italy

Hadassah Medical Center Jerusalem Israel

Hospital Clínico Universitario de Valencia Health Research Institute INCLIVA Spain

Hospital la Paz Madrid Spain

Lincoln Paris France

Ohio State University Columbus OH USA

PA Cervello EMAT Palermo Italy

Sanofi R and D Chilly Mazarin France

Sanofi R and D Vitry sur Seine France

University of Manchester and The Christie NHS Foundation Trust Manchester Academic Health Science Centre UK

University of Milan Italy

Vall d'Hebron Research Institute Barcelona Spain

Wojskowy Instytut Medyczny Warsaw Poland

Zobrazit více v PubMed

Sant M, Allemani C, Tereanu C, et al. Incidence of hematologic malignancies in Europe by morphologic subtype: results of the HAEMACARE project. Blood. 2010;116(19):3724–3734. PubMed

Montoto S, Fitzgibbon J. Transformation of indolent B-cell lymphomas. J Clin Oncol. 2011;29(14):1827–1834. PubMed

Dunleavy K, Wilson WH. Appropriate management of molecular subtypes of diffuse large B-cell lymphoma. Oncology (Williston Park). 2014;28(4):326–334. PubMed PMC

Green TM, Young KH, Visco C, et al. Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012;30(28):3460–3467. PubMed

Johnson NA, Slack GW, Savage KJ, et al. Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012;30(28):3452–3459. PubMed PMC

Tilly H, Gomes da SM, Vitolo U, et al. Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26 Suppl 5:v116–v125. PubMed

Staiger AM, Ziepert M, Horn H, et al. Clinical impact of the cell-of-origin classification and the MYC/BCL2 dual expresser status in diffuse large B-cell lymphoma treated within prospective clinical trials of the German High-Grade Non-Hodgkin’s Lymphoma Study Group. J Clin Oncol. 2017;35(22):2515–2526. PubMed

Petrella T, Copie-Bergman C, Briere J, et al. BCL2 expression but not MYC and BCL2 coexpression predicts survival in elderly patients with diffuse large B-cell lymphoma independently of cell of origin in the phase 3 LNH03-6B trial. Ann Oncol. 2017;28(5): 1042–1049. PubMed

Sehn LH, Berry B, Chhanabhai M, et al. The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood. 2007;109(5):1857–1861. PubMed

Zhou Z, Sehn LH, Rademaker AW, et al. An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era. Blood. 2014;123(6):837–842. PubMed PMC

Dunleavy K, Fanale M, Lacasce A, et al. Preliminary report of a multicenter prospective phase II study of DA-EPOCH-R in MYC-rearranged aggressive B-cell lymphoma. 56th American Society of Hematology (ASH) Annual Meeting and Exposition, San Francisco, CA, USA, December 6–9, 2014.

Wilson WH, Jung SH, Pitcher BN, et al. Phase III randomized Study of R-CHOP versus DA-EPOCH-R and molecular analysis of untreated diffuse large B-cell lymphoma: CALGB/Alliance 50303. Blood. 2016;128(22):469.

Vitolo U, Trneny M, Belada D, et al. Obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincri stine, and prednisone in previously untreated diffuse large B-cell lymphoma. J Clin Oncol. 2017:JCO2017733402. PubMed

Arakaki H, Nakazato T, Osada Y, Ito C, Aisa Y, Mori T. Comparison of R-CVP with R-CHOP for very elderly patients aged 80 or over with diffuse large B cell lymphoma. Ann Hematol. 2017;96(7):1225–1226. PubMed

Nolasco-Medina D, Reynoso-Noveron N, Mohar-Betancourt A, Aviles-Salas A, Garcia-Perez O, Candelaria M. Comparison of three chemotherapy regimens in elderly patients with diffuse large B cell lymphoma: experience at a single national reference center in Mexico. Biomed Res Int. 2016;2016: 9817606. PubMed PMC

Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010;28(27):4184–4190. PubMed PMC

Van Den Neste E, Schmitz N, Mounier N, et al. Outcomes of diffuse large B-cell lymphoma patients relapsing after autologous stem cell transplantation: an analysis of patients included in the CORAL study. Bone Marrow Transplant. 2017;52(2):216–221. PubMed

Raufi A, Ebrahim AS, Al-Katib A. Targeting CD19 in B-cell lymphoma: emerging role of SAR3419. Cancer Manag Res. 2013;5:225–233. PubMed PMC

Ribrag V, Dupuis J, Tilly H, et al. A dose-escalation study of SAR3419, an anti-CD19 antibody maytansinoid conjugate, administered by intravenous infusion once weekly in patients with relapsed/refractory B-cell non-Hodgkin lymphoma. Clin Cancer Res. 2014;20(1):213–220. PubMed

Younes A, Kim S, Romaguera J, et al. Phase I multidose-escalation study of the anti-CD19 maytansinoid immunoconjugate SAR3419 administered by intravenous infusion every 3 weeks to patients with relapsed/refractory B-cell lymphoma. J Clin Oncol. 2012;30(22):2776–2782. PubMed PMC

Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579–586. PubMed

Advani A, Coiffier B, Czuczman MS, et al. Safety, pharmacokinetics, and preliminary clinical activity of inotuzumab ozogamicin, a novel immunoconjugate for the treatment of B-cell non-Hodgkin’s lymphoma: results of a phase I study. J Clin Oncol. 2010;28(12):2085–2093. PubMed

Wiernik PH, Lossos IS, Tuscano JM, et al. Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin’s lymphoma. J Clin Oncol. 2008;26(30):4952–4957. PubMed

Witzig TE, Reeder CB, LaPlant BR, et al. A phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma. Leukemia. 2011;25(2):341–347. PubMed PMC

Witzig TE, Vose JM, Zinzani PL, et al. An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma. Ann Oncol. 2011;22(7):1622–1627. PubMed

Hernandez-Ilizaliturri FJ, Deeb G, Zinzani PL, et al. Higher response to lenalidomide in relapsed/refractory diffuse large B-cell lymphoma in nongerminal center B-cell-like than in germinal center B-cell-like phenotype. Cancer. 2011;117(22):5058–5066. PubMed

Friedberg JW, Sharman J, Sweetenham J, et al. Inhibition of Syk with fostamatinib dis-odium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood. 2010;115(13): 2578–2585. PubMed PMC

Dunleavy K, Pittaluga S, Czuczman MS, et al. Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. Blood. 2009;113(24):6069–6076. PubMed PMC

Coiffier B, Thieblemont C, de GS, et al. A phase II, single-arm, multicentre study of coltuximab ravtansine (SAR3419) and rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma. Br J Haematol. 2016;173(5):722–730. PubMed

Jacobsen ED, Sharman JP, Oki Y, et al. Brentuximab vedotin demonstrates objective responses in a phase 2 study of relapsed/refractory DLBCL with variable CD30 expression. Blood. 2015;125(9):1394–1402. PubMed

Palanca-Wessels MC, Czuczman M, Salles G, et al. Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study. Lancet Oncol. 2015;16(6):704–715. PubMed

Morschhauser F, Flinn I, Advani RH, et al. Preliminary results of a phase II randomized study (ROMULUS) of polatuzumab vedotin (PoV) or pinatuzumab vedotin (PiV) plus rituximab (RTX) in patients (Pts) with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL). American Society of Clinical Oncology (ASCO), Chicago, IL, USA, May 30-June 3, 2014. Abstract 8519.

Wagner-Johnston ND, Goy A, Rodriguez MA, et al. A phase 2 study of inotuzumab ozogamicin and rituximab, followed by autologous stem cell transplant in patients with relapsed/refractory diffuse large B-cell lymphoma. Leuk Lymphoma. 2015;56(10): 2863–2869. PubMed

Viardot A, Goebeler M, Hess G, et al. Treatment of relapsed/refractory diffuse large B-cell lymphoma with the bispecific T-cell engager (TiTE) antibody construct blinatumomab: primary analysis results from an open-label, Phase 2 study. 56th Amercian Society of Hematology (ASH) Annual Meeting and Exposition, San Francisco, CA, USA, December 6–9, 2014. Abstract 4460.

Goswami T, Forero A, Hamadani M, et al. Phase I/II study of MEDI-551, a humanized monoclonal antibody targeting CD19, in subjects with relapsed or refractory advanced B-cell malignancies. American Society of Clinical Oncology (ASCO), Chicago, IL, USA, June 1-5, 2012. Abstract 8065.

Jurczak W, Zinzani PL, Goy A, et al. Phase IIa study of single-agents MOR208 in patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma (NHL). ASCO Annual Meeting, Chicago, IL, USA, May 29–June 2, 2015. Abstract 8500.

Pettengell R, Coiffier B, Narayanan G, et al. Pixantrone dimaleate versus other chemotherapeutic agents as a single-agent salvage treatment in patients with relapsed or refractory aggressive non-Hodgkin lymphoma: a phase 3, multicentre, open-label, randomised trial. Lancet Oncol. 2012;13(7): 696–706. PubMed

Shain KH, Dalton WS, Tao J. The tumor microenvironment shapes hallmarks of mature B-cell malignancies. Oncogene. 2015;34(36):4673–4682. PubMed PMC

Pfeifer M, Zheng B, Erdmann T, et al. Anti-CD22 and anti-CD79B antibody drug conjugates are active in different molecular diffuse large B-cell lymphoma subtypes. Leukemia. 2015;29(7):1578–1586. PubMed

Promising Immunotherapeutic Modalities for B-Cell Lymphoproliferative Disorders

Zobrazit více v PubMed

ClinicalTrials.gov
NCT01472887